Liquid compositions of calcium acetate

ABSTRACT

The invention relates to an aqueous liquid composition of calcium acetate, sweetener, and taste masking agent. Also provided is a method for binding phosphorus within the gastrointestinal tract of an individual by administering to the individual an aqueous solution of at least calcium acetate.

This application claims priority to U.S. Application Ser. No.60/832,093, filed Jul. 21, 2006, which is hereby incorporated byreference in its entirety.

BACKGROUND OF THE INVENTION

A major focus of research and development efforts in the pharmaceuticalindustry is on the formulation of acceptable oral pharmaceuticalcompositions. More particularly, these efforts are concentrated onmaking oral pharmaceuticals that are palatable to the consumer. Chiefamong the concerns of pharmaceutical manufacturers in this area is thedevelopment of drugs that are as palatable as they are efficacious. Theimportance of these research efforts is greatest where thepharmaceuticals at issue are intended to ameliorate a patient's medicalcondition or alleviate their symptoms in cases of terminal illness.Renal diseases, such as chronic renal failure, are examples of suchillnesses.

In cases of chronic renal failure, hyperphosphatemia, or excessphosphorus retention, plays a major role in the development of secondaryhyperparathyroidism and osteodystrophy. Antacids or prescriptionmedications are commonly used to manage or prevent hyperphosphatemia bybinding dietary phosphorus and, thus, preventing its absorption into thegastrointestinal tract.

Phosphorous binders bind phosphorus in the form of a phosphorous ionwithin the stomach and intestines. This process is thought to resultfrom a chemical reaction between dietary phosphorus and the cationpresent in the binder compound. The reaction causes the formation ofinsoluble and hence unabsorbable phosphate compounds. The cation in somephosphorous binders is aluminum or calcium. Despite their capacity forbinding phosphorus, large quantities of antacids must be ingested over along period of time for them to be effective. Therefore, dosage size andpalatability are particularly important for patients with chronic renaldisease.

Prescription medications typically effective in managing or preventinghyperphosphatemia include calcium acetate. Calcium acetate treatment isone of the most effective methods for management of chronic renaldisease. When administered orally, calcium acetate is more effectivethan any other calcium-containing binder in binding phosphorus. Usedalone or in combination with other materials, calcium acetate bindsphosphorus in the gastrointestinal tract and reduces the percentage ofconsumed phosphorus (i.e., of a given “dose” of phosphorus) which isabsorbed into the bloodstream. This compound is most effective inreducing phosphorous absorption when it is administered close in time tofood consumption. Despite these benefits, calcium acetate treatmentsheretofore known in the art have not been without their drawbacks.

Calcium acetate is a solid, and to date, it is formulated in varioussolid dosage forms, such as pills and tablets. See, e.g., U.S. Pat. Nos.6,875,445, 4,870,105, and 6,576,665. However, dosage forms of calciumacetate present a two-fold clinical dilemma, particularly for dialysispatients, who are a significant patient population that is treated withcalcium acetate. On one hand, dialysis patients who may suffer fromrenal diseases such as end stage renal disease, find such solid dosageforms difficult to swallow due to their bulk size. The difficulty isexacerbated because such patients need to consume large dosages ofcalcium acetate, and consequently they must swallow many pills.Additionally, as mentioned above, such patients need to consume thepills prior to a meal. A third and equally undesirable characteristic ofcalcium acetate is that it has a repugnant bitter taste that is veryunpleasant to the palate and is difficult to mask. Because solid dosageforms of calcium acetate must be able to disintegrate in the intestine,oral consumption of calcium acetate pills formulated to achieve thisobjective often leave particles of calcium acetate in patients' mouths,which particles leave the characteristic bad taste.

On the other hand, calcium acetate is water soluble, and liquidformulations of calcium acetate might be thought to alleviate theabove-mentioned shortcomings of solid dosage forms of the drug. However,solutions of calcium acetate are many times more potently repugnant tothe palate than are solid dosage forms. Additionally, it is verydifficult to mask the taste of solubilized calcium acetate. Moreover,dialysis patients are restricted to limited fluid intake, and liquiddosage forms therefore could further complicate the patients' treatmentregimens.

Consequently, despite the clear benefits of calcium acetate-basedtreatments, patients will typically fail to take the proper doses oftheir medicine, or they will turn to antacids as an alternative to thesedifficult-to-swallow unpalatable medications. The inventors are unawareof any liquid formulation of calcium acetate that could overcome theshortcomings of solid dosage forms while simultaneously addressing theabove-mentioned hazards of liquid formulations. These considerationsthus evidence a need in the art for liquid formulations of calciumacetate that mask the unpleasant taste, and yet are so limited in volumeas to be efficacious in treating renal disease patients who areundergoing dialysis treatment.

SUMMARY OF THE INVENTION

The present invention satisfies this need and others by providing, inone embodiment, a liquid pharmaceutical composition comprising anaqueous solution of at least calcium acetate, at least one polyol, atleast one sweetener, and at least one taste masking agent. In otherembodiments, the liquid composition comprises about 7%, 8%, 9%, 10%,11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20% or 21% calcium acetate(w/v). In other embodiments, the liquid composition comprises about13-15%, 12-16%, or 11-17% calcium acetate (w/v); and in otherembodiments the liquid composition comprises about 14% or 14.3% calciumacetate (w/v). In yet other embodiments, the liquid compositioncomprises about 2%, 3%, 4%, 5%, or 6% calcium acetate (w/v).

In one embodiment, five milliliters (mL) of the inventive compositionprovides about 710 milligrams of hydrous calcium acetate; in anotherembodiment, five milliliters of the inventive composition provides about667 milligrams of anhydrous calcium acetate. In other embodiments, theinventive composition provides about 5-200 milliequivalents of calciumper five milliliters of composition. In other embodiments the inventivecomposition provides about 169 milligrams of calcium per fivemilliliters. In other embodiments, the inventive composition providesabout 8 or about 8.45 milliequivalents of calcium per five milliliters.In other embodiments, the liquid composition comprises about 20% (w/v)to about 50% (w/v) of polyol (also known as sugar alcohol), or about 15%(w/v) to about 50% (w/v) of polyol. Exemplary polyols that can be usedin the inventive compositions include sorbitol, xylitol, maltitol,glycerine, propylene glycol, erythritol and combinations thereof. Inother embodiments, the liquid composition comprises about 15% (w/v) toabout 40% (w/v) sorbitol or 15% (w/v) to about 25% (w/v) sorbitol, orabout 16% (w/v) to about 26% (w/v) sorbitol or about 18% (w/v) to about24% (w/v) sorbitol and in other embodiments, the liquid compositioncomprises about 21% (w/v) sorbitol. In other embodiments the liquidcomposition comprises about 15% (w/v) to about 40% (w/v) of acombination of sorbitol and maltitol. In other embodiments, the liquidcomposition comprises about 15% (w/v) to 25% (w/v) of maltitol and inother embodiments, the composition comprises about 20% (w/v) maltitol.In other embodiments the liquid composition comprises about 1% (w/v) toabout 25% (w/v) of glycerine, and in other embodiments the liquidcomposition comprises about 5% (w/v) glycerine. In other embodiments theliquid composition comprises about 1.5% to about 2.5% propylene glycol(w/v).

In other embodiments, the sweetener of the liquid composition is anartificial sweetener (also known in the art as a “high intensitysweetener”). Exemplary artificial sweeteners include sucralose,acesulfame potassium, aspartame, and the saccharins. In otherembodiments, the artificial sweetener is selected from sucralose andsaccharin. In other embodiments, the sucralose is present at aconcentration of about 0.35% (w/v); in other embodiments, theconcentration of sucralose is from about 0.1% (w/v) to about 0.8% (w/v).In other embodiments, the concentration of saccharin is about 0.05%(w/v) to about 0.25% (w/v) or 0.2% (w/v) to about 0.8% (w/v) and inother embodiments, the concentration of saccharin is about 0.15% (w/v).

A suitable taste masking agent for use in the inventive composition ismonoammonium glycyrrhizinate (Magnasweet). In embodiments of theinvention, monoammonium glycyrrhizinate is present in the composition atabout 0.05% (w/v) to about 0.3% (w/v) and in other embodiments,monoammonium glycyrrhizinate is present in the composition at about 0.2%(w/v) to about 0.8% (w/v). In other embodiments the monoammoniumglycyrrhizinate is present in the composition at about 0.25% (w/v).

The inventive composition may also contain a flavoring agent; suitableflavoring agents include berry flavor, root beer flavor, cream flavor,chocolate flavor, peppermint flavor, spearmint flavor and wintergreenflavor and combinations thereof. Suitable berry flavoring agents includeblack cherry, strawberry, cherry, blueberry, raspberry and the like.So-called “artificial” and “natural” flavoring agents are included. Theinventive composition may also comprise menthol flavor.

The inventive composition may also contain one or more preservatives;exemplary preservatives include methylparaben, propylparaben, sorbicacid, sodium benzoate, potassium sorbate and combinations thereof.

The inventive composition may also contain povidone. In someembodiments, the composition comprises about 0.5% (w/v) to 1.0% (w/v)povidone, and in other embodiments, the composition comprises 0.75%(w/v) povidone. In other embodiments, the composition comprises lessthan about 5% (w/v), or less than about 4% (w/v), or less than about 3%(w/v), or less than about 2% (w/v), or less than about 1% (w/v)povidone. An exemplary povidone that can be used in the inventivecompositions is Povidone 25.

In other embodiments, the above-described calcium acetate compositionsdo not contain one or more of the following ingredients: magnesium salt,calcium-peptide compounds (for example, so-called CPP-calcium), orpolyvinylpyrrolidone (also known as “PVP” and “Povidone”).

In one embodiment, the inventive aqueous composition comprises about7-21% (w/v) calcium acetate, sorbitol, glycerine, monoammoniumglycyrrhizinate, and sucralose. Such a composition may further compriseblack cherry flavor and menthol flavor. Such a composition may furthercomprise propylene glycol, methylparaben, and propylparaben.

In one embodiment, the inventive aqueous composition comprises about14.3% (w/v) calcium acetate, about 21% (w/v) sorbitol, about 5% (w/v)glycerine, about 0.25% (w/v) monoammonium glycyrrhizinate, and about0.35% (w/v) sucralose. Such a composition may further comprise blackcherry flavor and menthol flavor (exemplary amount for each flavoringagent is 0.2% (w/v)). Such a composition may further comprise propyleneglycol (exemplary concentration is 2% (w/v)), methylparaben (exemplaryconcentration 0.05% (w/v)) and propylparaben (exemplary concentration0.005% (w/v)). In other embodiments the amounts of black cherry andmenthol flavor are provided q.s. as needed.

In a preferred embodiment, the inventive aqueous composition comprisesabout 7-21% (w/v) calcium acetate, sorbitol, glycerine, monoammoniumglycyrrhizinate, and sucralose. Such a composition may further compriseblack cherry flavor and menthol flavor. Such a composition may furthercomprise propylene glycol, povidone, and methylparaben.

In a preferred embodiment, the inventive aqueous composition comprisesabout 14.3% (w/v) calcium acetate, about 21% (w/v) sorbitol, about 5%(w/v) glycerine, about 0.25% (w/v) monoammonium glycyrrhizinate, andabout 0.35% (w/v) sucralose. Such a composition may further compriseblack cherry flavor and menthol flavor (exemplary amount for eachflavoring agent is 0.2% (w/v)). Such a composition may further comprisepropylene glycol (exemplary concentration is 2% (w/v)), methylparaben(exemplary concentration 0.2% (w/v)) and povidone (exemplaryconcentration 0.75% (w/v)). In other embodiments the amounts of blackcherry and menthol flavor are provided q.s. as needed.

In a preferred embodiment, the inventive aqueous composition comprisesabout 7-21% (w/v) calcium acetate, maltitol, glycerine, monoammoniumglycyrrhizinate, and sucralose. Such a composition may further compriseblack cherry flavor and menthol flavor. Such a composition may furthercomprise propylene glycol, povidone, and methylparaben.

In a preferred embodiment, the inventive aqueous composition comprisesabout 14.3% (w/v) calcium acetate, about 20% (w/v) maltitol, about 5%(w/v) glycerine, about 0.25% (w/v) monoammonium glycyrrhizinate, andabout 0.35% sucralose. Such a composition may further comprise blackcherry flavor and menthol flavor (exemplary amount for each flavoringagent is 0.2% (w/v)). Such a composition may further comprise propyleneglycol (exemplary concentration is 2% (w/v)), methylparaben (exemplaryconcentration 0.2% (w/v)) and povidone (exemplary concentration 0.75%(w/v)). In other embodiments the amounts of black cherry and mentholflavor are provided q.s. as needed.

The invention also provides, in another embodiment, a method for bindingphosphorus within the gastrointestinal tract of an individual,comprising administering to the individual an aqueous calcium acetatesolution, as described above. In this regard, the present invention willbe useful in treating individuals in need of dialysis and/or sufferingfrom one or more of the following disorders: renal disease, kidneydisease, end stage renal disease, and chronic kidney disease.

Administration of the calcium acetate composition of the presentinvention according to the method described herein is associated withenhanced patient compliance and fewer side effects than is evident inadministering presently available calcium acetate medications andphosphorous binders. This improved patient compliance with aphosphate-binding agent will improve management of the disease process.

DETAILED DESCRIPTION

The present invention stems from the surprising discovery that calciumacetate can be formulated in a very low volume solution whilesimultaneously being effectively taste-masked. The liquid composition ofcalcium acetate according to the invention thus possesses a number ofadvantages over solid formulations of calcium acetate, and overcomeslimitations that would otherwise be encountered in attempts toadminister calcium acetate in liquid form.

First, the liquid composition obviates the need for patients to consumelarge numbers of pills by eliminating any calcium acetate pills. In thisregard, patients taking other medications can swallow pills with theliquid composition of this invention.

Second, the composition of this invention can be formulated in verysmall volumes, and it therefore contributes only a negligible amount offluid to dialysis patients' daily fluid intake.

Third, patients no longer have to swallow multiple calcium acetate pillstogether at the beginning of meals. Typically, the inventive compositioncan be ingested orally just before meals. Alternatively, the patientscan swallow the inventive composition at intervals throughout theirmeals, or just before and just after meals. Not having to swallowmultiple pills makes the overall treatment regimen a more pleasantexperience, thereby ensuring high levels of patient compliance.

Fourth, the inventive composition is palatable, i.e., has a good taste,and the taste of the calcium acetate is masked, which contributes tohigh levels of patient compliance.

Fifth, the inventive composition can be formulated to have a low caloriecontent and/or a low glycemic index compared with liquid pharmaceuticalformulations that are made using traditional sweeteners such as glucoseand fructose. The inventive compositions are therefore suitable foradministration to patients with diabetes. It is known in the art thatsugars have a calorie content of about 4 calories per gram. As mentionedabove, in the compositions of the present invention the sweetener cancomprise a so-called artificial sweetener (sucralose, saccharin, etc.),which imparts no or negligible calories. The polyol component of theinventive compositions also imparts some sweetness, but it is known inthe art that polyols (sugar alcohols) contribute fewer calories per gramthan simple sugars and also have a lower glycemic index than simplesugars. For example, sorbitol has about 2.6 calories per gram andmaltitol has about 3 calories per gram. In some embodiments, theinventive compositions of the invention have no more than about 1calorie per milliliter and in other embodiments the inventivecompositions have no more than about 0.8 calories per milliliter.

As discussed above, an advantage of the liquid composition is thatcalcium acetate can be formulated in very low volume solutions. Asdiscussed above, typical calcium acetate concentrations range from about7% (w/v) to about 21% (w/v), based on the total volume of thecomposition. In some embodiments, the concentration is from about 12%(w/v) to about 16% (w/v), and in other embodiments the concentration isabout 14% or about 14.3% (w/v). The calcium acetate in the inventivecomposition is in aqueous solution. In still other embodiments, thecalcium acetate concentration of the inventive composition is about 6%or 5% or 4% or 3% or 2% (w/v).

The liquid compositions typically supply an average dose of calciumacetate in about 10 mL or less. In some embodiments, the volume canrange from about 4 mL to about 7 mL. Illustrative of the volume of adose is a composition measuring about 5 mL, which delivers theequivalent of one (1) tablet of a solid calcium acetate formulation,i.e., pill. Such a 5 mL dose can supply about 710 milligrams of hydrouscalcium acetate, or about 667 milligrams of anhydrous calcium acetate.Thus, for example, merely a tablespoon of the present composition (i.e.,˜15 mL) would replace three (3) conventional calcium acetate pills. Inother embodiments, 5 mL supplies about 1.065 grams of hydrous calciumacetate or about 1.0 gram of anhydrous calcium acetate.

The composition of the invention comprises a taste masking agent. Sometaste masking agents known in the art are characterized additionally assweeteners. Regardless of whether a particular compound is recognizedfor imparting sweetness, it should at least possess the property ofbeing able to mask tastes in the mouth. An exemplary taste masking agentin this regard is monoammonium glycyrrhizinate (Magnasweet).

The inventive composition also comprises a sweetener. Various sweetenersare contemplated, including but not limited to simple sugars such assucrose, dextrose, fructose, maltose, and the like. In otherembodiments, the inventive composition is “low calorie” or “light”,“sugar-free”, or “calorie-free.” As discussed above, the sweetener inthe inventive compositions may be a so-called “artificial sweetener”(also known as “high-intensity sweetener”), such as sucralose,acesulfame potassium, saccharin, and aspartame, or any combinationthereof. The use of such artificial sweeteners is desirable for addingsweetness without the addition of calories. Also as discussed above, thepolyol in the inventive composition may also provide some sweetening andthe lower calorie content of polyols, and lower glycemic index (comparedto simple sugars) make the inventive compositions suitable for lowcalorie diets. Additionally, the inventive compositions that are lowcalorie and/or low glycemic index would be suitable for diabeticpatients.

One of skill in the art will recognize that the “sugar-free” means thata product contains no amount of, or only trivial or “physiologicallyinconsequential” amounts of sugars. In this regard, “sugar free” meansless than 0.5 g of sugars per serving. “Calorie free” means fewer than 5calories per serving. Examples of synonyms for “free” include “without,”“no” and “zero.” Those products sweetened only with artificialsweeteners and/or sugar alcohols (and containing no other sugars) can beclassified as “sugar-free.” The term “low calorie” is understood to mean40 calories or less per reference amount.

In one embodiment, the composition comprises the sweetener sucralose andthe polyol sorbitol, and the taste masking agent monoammoniumglycyrrhizinate. In another embodiment, the composition comprises thesweetener sucralose and the polyols sorbitol and maltitol, and the tastemasking agent monoammonium glycyrrhizinate. In another embodiment, thecomposition comprises the sweetener sucralose and the polyol maltitol,and the taste masking agent monoammonium glycyrrhizinate.

As discussed above, the composition of the invention contemplatesvarious concentrations of calcium acetate, a taste masking agent, and asweetener to achieve a palatable composition.

In other embodiments, the taste masking agent is present in aconcentration of about 0.05% (w/v) to about 0.8% (w/v) based on thetotal volume of the composition. Exemplary concentrations are about0.05%, 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.35%, 0.4%, 0.45%, 0.5%, 0.55%,0.6%, 0.65%, 0.7%, 0.75% and 0.8% (w/v). In other embodiments, the tastemasking agent is present in a concentration of about 0.2% (w/v) to about0.8% (w/v) based on the total volume of the composition. Exemplaryconcentrations are about 0.25%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7% and 0.8%(w/v).

A preferred composition prescribed by the foregoing considerations, andfor use in the methods described herein, comprises calcium acetate in aconcentration about 14% (w/v), maltitol in a concentration of about 20%(w/v), sucralose in a concentration of about 0.35% (w/v), andmonoammonium glycyrrhizinate in a concentration of about 0.25% (w/v),based upon the total volume of the composition.

A preferred composition prescribed by the foregoing considerations, andfor use in the methods described herein, comprises calcium acetate in aconcentration of about 14% (w/v), sorbitol in a concentration of about21% (w/v), sucralose in a concentration of about 0.35% (w/v), andmonoammonium glycyrrhizinate in a concentration of about 0.25% (w/v),based upon the total volume of the composition.

The inventive composition may also contain a flavoring agent; suitableflavoring agents include berry flavor, root beer flavor, cream flavor,chocolate flavor, peppermint flavor, spearmint flavor and wintergreenflavor and combinations thereof. Suitable berry flavoring agents includeblack cherry, strawberry, cherry, blueberry, raspberry and the like.So-called “artificial” and “natural” flavoring agents are included. Theinventive composition may also comprise menthol flavor. The amounts ofthe flavoring agents used will vary depending on taste preferences andthe other ingredients in the composition, but will be a very smallpercentage of the overall composition; for example, in Examples 1-4, theartificial black cherry flavor and menthol are each present at aconcentration of 0.2% (w/v). In a typical composition of the invention,the flavoring agents will typically make up no more than 1% (w/v) of thecalcium acetate composition.

Other ingredients which may be present in the liquid composition of thepresent invention include buffers, such as citric acid or itscorresponding salts; surfactants; thickeners (such as methylcellulose,carboxymethylcellulose, polyvinylpyrrolidone, and the like);preservatives (such as methyl and propyl parabens, and the like;anti-oxidants, such as benzoate salts, and the like; chelating agents,such as EDTA and its salts and the like). The amount and type ofpreservative present in the liquid composition of the invention can bedetermined as known by those of skill in the art. For example,methylparaben can be used in a concentration of from 0.01% (w/v) toabout 0.2% (w/v), or from about 0.1% (w/v) to about 0.3% (w/v) andpropylparaben can be used in a concentration of from about 0.001% (w/v)to about 0.05% (w/v). Povidone can be used in a concentration of about0.5% (w/v) to about 1.0% (w/v).

In a preferred embodiment, the concentration of methylparaben is about0.2% (w/v) and the concentration of povidone is about 0.75% (w/v). Inanother embodiment, the composition of methylparaben is about 0.05%(w/v) and the concentration of propylparaben is about 0.005% (w/v); inanother embodiment, the composition of methylparaben is about 0.01%(w/v) and the concentration of propylparaben is about 0.025% (w/v).

As discussed above, the inventive compositions also include liquidcalcium acetate compositions that do not contain one or more of thefollowing ingredients: magnesium salt, calcium-peptide compounds (forexample, so-called CPP-calcium), or polyvinylpyrrolidone (PVP).

In various embodiments, the inventive composition can be formulated tohave a final pH of about 6.0 to about 7.0. Alternatively, the pH can beabout 6.0 to about 7.2. In one embodiment, the pH of the inventivecomposition is about 6.8.

Any of the embodiments of the liquid composition herein described aresuitable for use in the inventive method for binding phosphorus withinthe gastrointestinal tract of an individual. The method comprisesadministering to the individual an aqueous solution of at least calciumacetate as described herein. The administration, in one embodiment, isvia oral ingestion of the composition. As discussed, the use of calciumacetate to treat hyperphosphatemia is well known in the art, and hencethe dosages required to treat this condition can also be readilydetermined depending on patient condition, history and need. In thisregard, as discussed above, the typical dose of calcium supplied bycalcium acetate is on the order of about 10 to about 200milliequivalents of calcium per dose. A typical dosage regimen of theinventive composition is about one tablespoon (about 15 mL) three timesper day, which can be varied depending on the needs of the patient.

Furthermore, those of skill in the art will understand that the dose orquantity to be taken at a given time varies on an individual basis andcan be adjusted as needed, for example by monitoring the serum levels ofphosphorus and calcium. In this regard, the inventive compositions arepreferably administered close in time to food and/or beverageconsumption. In one embodiment, a dose of the inventive composition istaken orally just before meal ingestion and another dose is taken orallyjust after meal ingestion. As discussed herein, the entire doseadministered around a meal may all be taken just prior to ingestion of ameal.

In some embodiments, the individual to be treated is in need of dialysistreatment and hence may be undergoing such dialysis treatment. Invarious embodiments, the individual is suffering from a renal disease,such as, for example, end stage renal disease or chronic kidney disease.

The following examples are intended to illustrate the invention as ishereinabove more generally described, and therefore they should not beconstrued to limit the scope of the invention. Furthermore, alldocuments cited herein, including U.S. patents, are fully incorporatedas if fully set forth herein.

Example 1 General Procedure to Prepare Calcium Acetate LiquidComposition

Calcium acetate and a sweetener are dissolved in water. Flavoring andglycerin USP are mixed with each other to eventually obtain ahomogeneous solution. A taste masking agent is added to and mixed withthe calcium acetate solution. Parabens preservatives are dissolved inpropylene glycol. Optionally an additional taste masking or sweeteningagent is mixed with the calcium acetate solution. All solutionsincluding any other polyols are agitated together and purified water isadded q.s. to achieve a homogeneous solution.

Example 2 Calcium Acetate Liquid Compositions

Following the general procedure of Example 1, a 1.0 L liquid calciumacetate composition was prepared using the following concentrations andproportions of components:

Component Amount % w/v Sorbitol solution (70%) 300 g 30 Calcium acetateUSP 143 g 14.3 Glycerine USP 50 g 5 Propylene Glycol USP 20 g 2Magnasweet 110 (10% solution) 25 g 2.5% Sucralose 3.5 g 0.35Methylparaben NF 0.5 g 0.05 Propylparaben NF 0.05 g 0.005 Artificialblack cherry flavor 2 g 0.2 Menthol flavor 2 g 0.2 Purified water USPq.s. 1000 ml

Note that because a 70% solution of sorbitol was used, the % of sorbitolcompound in the final composition is 21%. This composition containsabout 0.5 calories per milliliter. Multiple people tasted thiscomposition at typical dosage levels, and all people who tested thiscomposition rated the composition as palatable and/or having “good”flavor. It was determined that this composition would be suitable foradministration to patients and that those patients would be expected tocomply well with their medication requirements, given the qualities ofthe composition (including but not limited to, palatability and lowvolume of liquid with high concentration of calcium). For those patientsneeding to limit calorie intake, this composition is suitable because ofits low calorie content.

In another example, the calcium acetate liquid composition of thisexample is formulated using 0.1% (w/v) methylparaben and 0.025% (w/v)propylparaben. In yet another example, the flavoring agents are addedq.s. to achieve a palatable taste with the minimum effective amount offlavoring agent.

Example 3

Following the general procedure of Example 1, a 1.0 L liquid calciumacetate composition was prepared using the following concentrations andproportions of components:

Component Amount % w/v Sorbitol solution (70%) 300 g 30 Calcium acetateUSP 143 g 14.3 Glycerine USP 50 g 5 Propylene Glycol USP 20 g 2Magnasweet 110 (10% solution) 25 g 2.5 Sucralose 3.5 g 0.35 Povidone 25,USP 7.5 g 0.75 Methylparaben NF 2 g 0.2 Artificial black cherry flavor 2g 0.2 Menthol flavor 2 g 0.2 Purified water USP q.s. 1000 ml

Note that because a 70% solution of sorbitol was used, the % of sorbitolcompound in the final composition is 21%. This composition containsabout 0.5 calories per milliliter. Multiple people tasted thiscomposition at typical dosage levels, and all people who tested thiscomposition rated the composition as palatable and/or having “good”flavor. It was determined that this composition would be suitable foradministration to patients and that those patients would be expected tocomply well with their medication requirements, given the qualities ofthe composition (including but not limited to, palatability and lowvolume of liquid with high concentration of calcium). For those patientsneeding to limit calorie intake, this composition is suitable because ofits low calorie content.

Example 4

Following the general procedure described below, a 2.0 L liquid calciumacetate composition was prepared using the following concentrations andproportions of components:

Component Amount % w/v Maltitol (crystalline) 400 g 20 Calcium acetateUSP 286 g 14.3 Glycerine USP 100 g 5 Propylene Glycol USP 40 g 2Magnasweet 110 (10% solution) 50 g 2.5 Sucralose 7 g 0.35 Povidone 25USP 15 g 0.75 Methylparaben NF 4 g 0.2 Artificial black cherry flavor 4g 0.2 Menthol flavor 4 g 0.2 Purified water USP q.s. 2000 ml

Calcium acetate was dissolved in 1 liter of water and sucralose wasadded to this aqueous mixture, followed by the addition of maltitol withagitation, then glycerin, then Magnasweet with agitation and thenPovidone was added and mixed until dissolved. Methylparaben wasdissolved in propylene glycol and added to the aqueous mixture withagitation. The flavors were then added with agitation. Additional waterwas added to bring the total volume to 2 liters.

This composition contains about 0.4 calories per milliliter. Multiplepeople tasted this composition at typical dosage levels, and all peoplewho tested this composition rated the composition as palatable and/orhaving “good” flavor. It was determined that this composition would besuitable for administration to patients and that those patients would beexpected to comply well with their medication requirements, given thequalities of the composition (including but not limited to, palatabilityand low volume of liquid with high concentration of calcium). For thosepatients needing to limit calorie intake, this composition is suitablebecause of its low calorie content.

What is claimed is:
 1. An oral dosage form of calcium acetate comprisinga liquid pharmaceutical composition comprising an aqueous solution of:(a) 7-16% calcium acetate (w/v), (b) an artificial sweetener selectedfrom the group consisting of sucralose, acesulfame potassium, aspartameand saccharin, (c) a polyol selected from the group consisting ofsorbitol, glycerine, propylene glycol, xylitol, maltitol, andcombinations thereof, and (d) a taste masking agent comprisingmonoammonium glycyrrhizinate.
 2. The oral dosage form according to claim1, wherein the calcium acetate is present in a concentration of fromabout 12% (w/v) to about 16% (w/v) based on the total volume of thecomposition.
 3. The oral dosage form according to claim 2, wherein thecalcium acetate is present in a concentration of about-14% (w/v).
 4. Theoral dosage form according to claim 1, wherein the total concentrationof polyol is from about 15% (w/v) to about 50% (w/v) based on the totalvolume of the composition.
 5. The oral dosage form according to claim 1,wherein said composition comprises from about-15% (w/v) to about 40%(w/v) of sorbitol.
 6. The oral dosage form according to claim 1, whereinsaid composition comprises about 21% (w/v) sorbitol.
 7. The oral dosageform according to claim 1, wherein said composition comprises from about15% (w/v) to about 25% (w/v) maltitol.
 8. The oral dosage form accordingto claim 7, wherein said composition comprises about 20% (w/v) maltitol.9. The oral dosage form according to claim 6, wherein said compositionfurther comprises from about 1% (w/v) to about 25% (w/v) of glycerine.10. The oral dosage form according to claim 9, wherein the glycerine ispresent at a concentration of about 5% (w/v).
 11. The oral dosage formaccording to claim 1, wherein said artificial sweetener is selected fromthe group consisting of sucralose and saccharin.
 12. The oral dosageform according to claim 11, wherein said sucralose is present at aconcentration of about 0.35% (w/v) or said saccharin is present at aconcentration of about 0.15% (w/v).
 13. The oral dosage form accordingto claim 1, further comprising at least one flavoring agent.
 14. Theoral dosage form according to claim 13, wherein said flavoring agent isselected from the group consisting of berry flavor, root beer flavor,cream flavor, chocolate flavor, peppermint flavor, spearmint flavor andwintergreen flavor.
 15. The oral dosage form according to claim 14,further comprising menthol flavor.
 16. The oral dosage form according toclaim 13, wherein said flavoring agent is black cherry flavor.
 17. Theoral dosage form according to claim 16, wherein said black cherry flavoris artificial black cherry flavor.
 18. The oral dosage form according toclaim 1, further comprising at least one preservative.
 19. The oraldosage form according to claim 18, wherein said preservative is selectedfrom the group consisting of: methylparaben, propylparaben, sorbic acid,sodium benzoate, potassium sorbate and combinations thereof.
 20. Theoral dosage form according to claim 19, wherein said preservative ismethylparaben.
 21. The oral dosage form according to claim 20, furthercomprising polyvinylpyrrolidone (PVP).
 22. The oral dosage formaccording to claim 18, wherein said polyol comprises propylene glycol.23. The oral dosage form according to claim 1, wherein the pH of thecomposition is from about 6.0 to about 7.2.
 24. The oral dosage formaccording to claim 1, comprising about 21% (w/v) sorbitol, about 14%(w/v) calcium acetate, about 5% (w/v) glycerine, about 2% (w/v)propylene glycol, about 0.25% (w/v) monoammonium glycyrrhizinate, about0.35% (w/v) sucralose, about 0.75% (w/v) polyvinylpyrrolidone, about0.2% (w/v) methylparaben, about 0.2% (w/v) artificial black cherryflavor, and about 0.2% (w/v) menthol flavor.
 25. The oral dosage formaccording to claim 1, comprising about 20% (w/v) maltitol, about 14%(w/v) calcium acetate, about 5% (w/v) glycerine, about 2% (w/v)propylene glycol, about 0.25% (w/v) monoammonium glycyrrhizinate, about0.35% (w/v) sucralose, about 0.75% (w/v) polyvinylpyrrolidone, about0.2% (w/v) methylparaben, about 0.2% (w/v) artificial black cherryflavor, and about 0.2% (w/v) menthol flavor.
 26. The oral dosage form ofclaim 1, wherein 5 milliliters of said composition contains about 710milligrams of hydrous calcium acetate.
 27. The oral dosage form of claim1, wherein 5 milliliters of said composition contains about 667milligrams of anhydrous calcium acetate.
 28. The oral dosage form ofclaim 1, wherein 5 milliliters of said composition contains about 169milligrams of calcium.
 29. The oral dosage form of claim 1, wherein saidcomposition is sugar-free.
 30. The oral dosage form of claim 1, whereinsaid composition is low-calorie.
 31. The oral dosage form of claim 1,wherein said composition is calorie-free.
 32. The oral dosage form ofclaim 1, which comprises about 8 milliequivalents of calcium.
 33. Amethod for binding phosphorus within the gastrointestinal tract of anindividual, comprising orally administering to said individual a liquidpharmaceutical composition comprising an aqueous solution comprising:from 7% (w/v) to 16% (w/v) of calcium acetate, an artificial sweetenerselected from the group consisting of sucralose, acesulfame potassium,aspartame and saccharin, a polyol selected from the group consisting ofsorbitol, glycerine, propylene glycol, xylitol, maltitol, andcombinations thereof, and a taste masking agent comprising monoammoniumglycyrrhizinate.
 34. The method according to claim 33, wherein theindividual is in need of dialysis and/or is suffering from one or moreof the following disorders: renal disease, kidney disease, end stagerenal disease, chronic kidney disease.
 35. The method according to claim33, wherein the composition comprises: calcium acetate in aconcentration of about 12% (w/v) to about 16% (w/v) based on the totalvolume of the composition.
 36. The method according to claim 33, whereinthe calcium acetate is present in a concentration of about 14% (w/v).37. The method according to claim 33, wherein the total concentration ofpolyol in the composition is about 15% (w/v) to about 50% (w/v) based onthe total volume of the composition.
 38. The method according to claim33, wherein said composition comprises about 15% (w/v) to about 40%(w/v) of sorbitol based on the total volume of the composition.
 39. Themethod according to claim 33, wherein said composition comprises about21% (w/v) sorbitol.
 40. The method according to claim 33, wherein saidcomposition comprises about 15% (w/v) to about 25% (w/v) maltitol basedon the total volume of the composition.
 41. The method according toclaim 33, wherein said composition comprises about 20% (w/v) maltitol.42. The method according to claim 33, wherein said composition furthercomprises about 1% (w/v) to about 25% (w/v) of glycerine based on thetotal volume of the composition.
 43. The method according to claim 42,wherein said glycerine is present at a concentration of about 5% (w/v).44. The method according to claim 33, wherein said artificial sweeteneris selected from the group consisting of sucralose and saccharin. 45.The method according to claim 44, wherein said sucralose is present at aconcentration of about 0.35% (w/v) or said saccharin is present at aconcentration of about 0.15% (w/v) based on the total volume of thecomposition.
 46. The method according to claim 33, wherein saidcomposition further comprises at least one flavoring agent.
 47. Themethod according to claim 46, wherein said flavoring agent is selectedfrom the group consisting of menthol, berry flavor, root beer flavor,cream flavor, chocolate flavor, peppermint flavor, spearmint flavor andwintergreen flavor.
 48. The method according to claim 47, wherein saidflavoring agent is black cherry flavor.
 49. The method according toclaim 48, wherein said black cherry flavor is artificial black cherryflavor.
 50. The method according to claim 48, wherein said compositionfurther comprises menthol flavor.
 51. The method according to claim 33,wherein said composition further comprises at least one preservative.52. The method according to claim 51, wherein said preservative isselected from the group consisting of methylparaben, propylparaben,sorbic acid, sodium benzoate, potassium sorbate and combinationsthereof.
 53. The method according to claim 52, wherein said preservativecomprises methylparaben.
 54. The method according to claim 33, whereinsaid composition comprises polyvinylpyrrolidone (PVP).
 55. The methodaccording to claim 33, wherein said polyol comprises propylene glycol.56. The method according to claim 33, wherein said composition has pH ofabout 6.0 to about 7.2.
 57. The method of claim 33, wherein saidcomposition comprises about 21% (w/v) sorbitol, about 14% (w/v) calciumacetate, about 5% (w/v) glycerine, about 2% (w/v) propylene glycol,about 0.25% (w/v) monoammonium glycyrrhizinate, about 0.35% (w/v)sucralose, about 0.75% (w/v) polyvinylpyrrolidone, about 0.2% (w/v)methylparaben, about 0.2% (w/v) artificial black cherry flavor, andabout 0.2% (w/v) menthol flavor.
 58. The method of claim 33, whereinsaid composition comprises about 20% (w/v) maltitol, about 14% (w/v)calcium acetate, about 5% (w/v) glycerine, about 2% (w/v) propyleneglycol, about 0.25% (w/v) monoammonium glycyrrhizinate, about 0.35%(w/v) sucralose, about 0.75% (w/v) polyvinylpyrrolidone, about 0.2%(w/v) methylparaben, about 0.2% (w/v) artificial black cherry flavor,and about 0.2% (w/v) menthol flavor.
 59. The method of claim 33, wherein5 milliliters of said composition contains about 710 milligrams ofhydrous calcium acetate.
 60. The method of claim 33, wherein 5milliliters of said composition contains about 667 milligrams ofanhydrous calcium acetate.
 61. The method of claim 33, wherein 5milliliters of said composition contains about 169 milligrams ofcalcium.
 62. The method of claim 33, wherein said composition issugar-free.
 63. The method of claim 33, wherein said composition is alow-calorie composition.
 64. The method of claim 33, wherein saidcomposition is calorie-free.
 65. The method of claim 33, wherein saidcomposition comprises about 8 milliequivalents of calcium.
 66. Themethod according to claim 33, wherein the individual is suffering fromhyperphosphatemia.
 67. The method according to claim 33, wherein themethod comprises administering about one tablespoon (15 mL) of saidcomposition three times per day.
 68. The method according to claim 33,wherein the method comprises administering said composition around thetime of ingestion of a meal.